<p> This is a dissertation on the neurodegenerative tauopathy corticobasal degeneration (CBD). Because CBD is a rare disorder and has <50% antemortem diagnostic accuracy, we sought to learn as much as possible from our invaluable resource, having the largest, single neuropathologically-confirmed CBD cohort in the world. This is a culmination of several different projects, all focused on neuropathologic, genetic, and clinical features of CBD, with the overall intent being to help patients who will suffer from this devastating disorder. Each study/chapter had a specific hypothesis, aimed to elucidate various unanswered questions about CBD. Essentially, the only possible approach to further our understanding of CBD is what we have done here: use patient tissue and DNA samples who have donated their brains to research. </p><p> <u>Richardson syndrome is one of the most common clinical presentations of CBD:</u> Clinicopathologic assessment of CBD patients presenting with Richardson syndrome (CBD-RS) (i.e. patients misdiagnosed as progressive supranuclear palsy), identified neuropathologic and clinical signs and symptoms that were able to differentiate CBD-RS from PSP patients. Digital microscopy and image analysis were used to quantify tau pathology in multiple brain regions and found CBD-CBS (corticobasal syndrome) cases had greater peri-Rolandic tau burden and CBD-RS had greater hindbrain and limbic tau pathology. CBD-RS patients exhibited a frontal/dysexecutive syndrome and urinary incontinence more often than PSP patients. We also describe an unusual variant of CBD with olivopontocerebellar atrophy, of which two of the patients presented with Richardson syndrome and had greater hindbrain tau pathology than CBD-CBS, and interestingly had significant TDP-43 (protein inclusions found in FTLD and ALS) pathology in affected regions. Regarding TDP-43 pathology in CBD, we found that >25% of cases have TDP-43 immunoreactive neuronal and glial cytoplasmic inclusions and threads, and the greatest burden was in the basal ganglia. With these studies we were able to show that Richardson syndrome is one of the most common clinical presentations of CBD.</p><p> Identification of a novel MAPT mutation (p.N410H) in a CBD case that is neuropathologically indistinguishable from sporadic CBD: We screened our autopsy-confirmed CBD cohort for MAPT mutations and identified a novel mutation in MAPT exon 13 (p.N410H) in a case that is neuropathologically indistinguishable from sporadic CBD. This is not only the first MAPT mutation identified to cause CBD, but it is also the first mutation to cause CBD. Functional studies with this mutation showed that there was decreased ability for mutant tau to promote microtubule assembly and exhibited a marked increase in filament formation in vitro. In this study we also identified two rare variants in the 3' untranslated regulatory region of MAPT that associate with CBD, and one of these variants also associated with PSP. CBD and PSP have shared and unique genetic risk factors: Our last study as part of my dissertation, is the first ever CBD genome-wide association study. We performed a discovery stage, replication stage, and meta-analysis in 152 CBD cases versus 3,111 control individuals (discovery), with 67 CBD cases versus 457 controls (replication). This identified two genome genome-wide significant associations with CBD at MAPT and KIF13B/DUSP4. Using a candidate gene approach, we tested for CBD association with the top progressive supranuclear palsy GWAS SNPs. This identified strong associations at MOBP and MAPT H1c haplotype. Another novel genetic association for CBD patients was identified at SOS1. Expression/SNP associations were tested from ~400 brain samples of cerebellum and temporal cortex and found significant associations at MAPT, MOBP, and SOS1. The genome-wide significant association at KIF13B/DUSP4 with CBD will require additional studies to determine which gene is responsible for the association signal. In summary, these findings show for the first time, that CBD and PSP share common genetic variation, other than MAPT, at MOBP which confers disease risk. Together, warranting future studies to understand the mechanism by which MOBP contributes to the CBD and PSP disease processes.</p>
| Identifer | oai:union.ndltd.org:PROQUEST/oai:pqdtoai.proquest.com:3702551 |
| Date | 23 May 2015 |
| Creators | Kouri, Naomi |
| Publisher | College of Medicine - Mayo Clinic |
| Source Sets | ProQuest.com |
| Language | English |
| Detected Language | English |
| Type | thesis |
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